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PubMed2003

VE-statin, an endothelial repressor of smooth muscle cell migration.

The recruitment and proliferation of smooth muscle cells and pericytes are two key events for the stabilization of newly formed capillaries during angiogenesis and, when out of control in the adult, are the main causes of arteriosclerosis. We have identified a novel gene, named VE-statin for vascular endothelial-statin, which is expressed specifically by endothelial cells of the developing mouse embryo and in the adult, and in early endothelial progenitors. The mouse and human VE-statin genes have been located on chromosome 2 and 9, respectively, they span >10 kbp and are transcribed in two major variants arising from independent initiation sites. The VE-statin transcripts code for a unique protein of 30 kDa that contains a signal peptide and two epidermal growth factor (EGF)-like modules. VE-statin is found in the cellular endoplasmic reticulum and secreted in the cell supernatant. Secreted VE-statin inhibits platelet-derived growth factor (PDGF)-BB-induced smooth muscle cell migration, but has no effects on endothelial cell migration. VE-statin is the first identified inhibitor of mural cell migration specifically produced by endothelial cells.

Amino Acid Sequence↗
PubMed2006

A new phylogenetic lineage of rabies virus associated with western pipistrelle bats (Pipistrellus hesperus).

Bats represent the major source of human rabies cases in the New World. In the USA, most cases are associated with species that are not commonly found or reported rabid. To understand better the epidemiology and public health significance of potentially important bat species, a molecular study was performed on samples collected from naturally infected rabid western pipistrelle (Pipistrellus hesperus), eastern pipistrelle (Pipistrellus subflavus) and silver-haired bats (Lasionycteris noctivagans) from different regions of their geographical distribution in the USA. A 264 bp fragment at the 5' end of the N gene coding region was sequenced and analysed in comparison with rabies virus variants circulating within other North American mammals. Phylogenetic analysis demonstrated that P. hesperus bats maintain a unique rabies virus variant. Preliminary data also suggest that P. subflavus and Lasionycteris noctivagans may harbour two different rabies virus variants (Ps and Ln) that are likely to be maintained independently by each bat species, which recently appear to have emerged as major vectors of human disease.

Amino Acid Sequence↗
PubMed2025

Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.

OBJECTIVES: Nonsyndromic orofacial clefts (OFCs) involve complex genetic and environmental factors, with over 60 risk loci accounting for only a minority of estimated heritability and residing in non-coding regions with unclear functional relevance. We hypothesize that some genetic variants alter orofacial cleft risk by modifying DNA methylation (DNAm) at regulatory sequences essential for craniofacial development, acting as methylation quantitative trait loci (meQTLs). METHODS: We analyzed 10 well-established OFC-associated SNPs against genome-wide DNAm profiles in 409 cases and 456 controls, identifying 23 potential meQTLs. We validated findings using 358 cleft-discordant sibling pairs analyzed with quantitative MethyLight assays. Cross-referencing with the mQTL Database assessed temporal patterns across human development. Functional annotation used GeneHancer and craniofacial enhancer databases. RESULTS: Nine meQTLs were successfully replicated, including the highly significant rs987525 (8q24) - cg16561172 (MYC) association (P = 9.610E-6). This association mapped to a mesendoderm-active enhancer upstream of MYC, providing mechanistic explanation for the longstanding 8q24 cleft locus. Additional validated associations involved MAFB-PLCG1, NOG-PPM1E, FOXE1-FRZB, and SPRY2-LGR4 interactions. Independent differential methylation analysis revealed significant differences between discordant siblings at three CpG sites. Cross-referencing confirmed concordance with population-level methylation effects, with childhood representing the critical developmental window for most associations. CONCLUSIONS: This systematic meQTL characterization in OFCs demonstrates that genetic variants influence disease risk through epigenetic mechanisms. The 8q24-MYC regulatory pathway evidence provides crucial mechanistic insight into a major OFC risk locus. These findings bridge genetic associations with functional consequences, address missing heritability challenges, and suggest potential biomarkers and therapeutic targets for OFC prevention and treatment.

Journal Article↗
PubMed2001

Dewetting hydrodynamics in 1+1 dimensions.

A model for the phase transition between partial wetting and dewetting of a substrate has been formulated that explicitly incorporates the hydrodynamic flow during the dewetting process in 1+1 dimensions. The model simulates a fluid layer of finite thickness on a substrate in coexistence with a dry part of the substrate and a gas phase above the substrate. Under nonequilibrium "dewetting" conditions, the front between the dry part and the wet part of the surface moves towards the wet part inducing hydrodynamic flow inside the wet layer. In more general terms, the model handles two immiscible fluids with a freely movable interface in an inhomogeneous external force field. Handling the interface by a new variant of the phase-field model, we obtain an efficient code with well-defined interfacial properties. In particular, the (free) energy can be chosen at will. We demonstrate that our model works well in the viscosity range of creeping flow and we give qualitative results for the higher Reynolds numbers. Connections to experimental realizations are discussed.

Journal Article↗
PubMed1993

Bovine casein haplotypes: number, frequencies and applicability as genetic markers.

Three casein loci, tightly linked on bovine chromosome 6, have been studied as haplotypes within families of bulls. The polymorphisms included in the study were CASAS1 (B, C), CASB (A1, A, A5, B), CASK (A, B, E) and a microsatellite in intron III of CASK. A new A5 variant of CASB, caused by a silent mutation in the triplet coding for amino acid 110, was detected by direct polymerase chain reaction sequencing. Our analysis of 306 sons and 15 sires revealed 10 different casein haplotypes with a cumulative polymorphic information content (PIC) of 0.78.

Animals↗
PubMed1987

Antigenic and structural properties of the hemagglutinin-neuraminidase glycoprotein of human parainfluenza virus type 3: sequence analysis of variants selected with monoclonal antibodies which inhibit infectivity, hemagglutination, and neuraminidase activities.

The hemagglutinin-neuraminidase (HN) gene sequence was determined for 16 antigenic variants of human parainfluenza virus type 3 (PIV3). The variants were selected by using monoclonal antibodies (MAbs) to the HN protein which inhibit neuraminidase, hemagglutination, or both activities. Each variant had a single-point mutation in the HN gene, coding for a single amino acid substitution in the HN protein. Operational and topographic maps of the HN protein correlated well with the relative positions of the substitutions. There was little correlation between the cross-reactivity of a MAb with the bovine PIV3 HN and the amount of amino acid homology between the human and bovine PIV3 HN proteins in the regions of the epitopes, suggesting that many of the epitopes are conformational in nature. Computer-assisted analysis of the HN protein predicted a secondary structure composed primarily of hydrophobic beta sheets interconnected by random hydrophilic coil structures. The HN epitopes were located in predicted coil regions. Epitopes recognized by MAbs which inhibit neuraminidase activity of the virus were located in a region which appears to be structurally conserved among several paramyxovirus HN proteins and which may represent the sialic cid-binding site of the HN molecule.

Amino Acid Sequence↗
PubMed1994

Woodchuck hepatitis virus X protein is required for viral infection in vivo.

The X gene of the mammalian hepadnaviruses is believed to encode a protein of 17 kDa which has been shown to transactivate a wide range of viral and cellular promoters. The necessity for X gene expression during the viral life cycle in vivo has recently been suggested (H.-S. Chen, S. Kaneko, R. Girones, R. W. Anderson, W. E. Hornbuckle, B. C. Tennant, P. J. Cote, J. L. Gerin, R. H. Purcell, and R. H. Miller, J. Virol. 67:1218-1226, 1993). We have independently constructed two variants of woodchuck hepatitis virus (WHV) with mutations in the X coding region. Transient transfection of two different hepatoma cell lines showed that these WHV X gene mutants were competent for virus replication in vitro. To determine whether X expression was required for viral replication in vivo, we injected mutant and wild-type genomes into the livers of susceptible woodchucks. While the wild-type WHV genomes were infectious in all animals examined, the mutant genomes did not initiate a WHV infection in woodchucks. These results indicate that the X gene of the hepadnaviruses plays a major role in viral replication in vivo.

Animals↗
PubMed2006

Of flies and man: Drosophila as a model for human complex traits.

Understanding the genetic and environmental factors affecting human complex genetic traits and diseases is a major challenge because of many interacting genes with individually small effects, whose expression is sensitive to the environment. Dissection of complex traits using the powerful genetic approaches available with Drosophila melanogaster has provided important lessons that should be considered when studying human complex traits. In Drosophila, large numbers of pleiotropic genes affect complex traits; quantitative trait locus alleles often have sex-, environment-, and genetic background-specific effects, and variants associated with different phenotypic are in noncoding as well as coding regions of candidate genes. Such insights, in conjunction with the strong evolutionary conservation of key genes and pathways between flies and humans, make Drosophila an excellent model system for elucidating the genetic mechanisms that affect clinically relevant human complex traits, such as alcohol dependence, sleep, and neurodegenerative diseases.

Animals↗
PubMed1993

In humans all U3 genes map to chromosome 17p12-->p11, but in mouse the U3A and U3B genes are located on different chromosomes.

U3 small nucleolar RNA, which participates in eukaryotic rRNA processing, is encoded by a small multigene family in mammals. In humans, the four to six gene copies code for an identical U3 RNA molecule; rodents, however, have two variant forms of these genes, U3A and U3B. We show that all U3 genes in humans map to a single chromosomal locus, 17p12-->-p11, which corresponds exactly to the region of mouse Chromosome 11 where the four U3B genes are clustered. By contrast, in mouse the unique U3A gene copy is not linked to the U3B gene cluster but maps to another chromosome (the B2-B4 region of Chromosome 10).

Animals↗
PubMed1995

Vibrio cholerae in the horn of Africa: epidemiology, plasmids, tetracycline resistance gene amplification, and comparison between O1 and non-O1 strains.

The prevalence of Vibrio cholerae O1 and non-O1 has been investigated in numerous Somali regions of the Horn of Africa from 1983 to 1990. From January 1983 to January 1985 and between December 1986 and December 1990, no strains of V. cholerae O1 and 226 strains (5.3%) of V. cholerae non-O1 were isolated from 4,295 diarrhea cases. During a cholera epidemic in 1985 and 1986, the overall case-fatality rate was 13% and the attack rate was 3-3.5 per 1,000 population. Matched case-control studies identified a waterborne route of transmission. A drug-susceptible Ogawa strain from Ethiopia caused the introduction of the disease into northern Somalia. There were two major resistant derivatives of the original strain, and the one resistant to ampicillin, kanamycin, streptomycin, sulfonamide, and tetracycline (TC) predominated in the spreading disease. In 1986, susceptible Ogawa strains quickly displaced this resistant strain. The two incompatibility group C plasmids responsible for the resistance patterns had complex and scattered differences in their structures. Physical analysis of the plasmid DNA region coding for TC resistance demonstrated its genetic amplification in highly resistant variants of Ogawa strains.

Adolescent↗
PubMed1998

Identification of two rare variants (G-->A at nucleotide 721; C-->T at nucleotide 5200) in the rhodopsin gene. Mutations in brief no. 187. Online.

The authors report two new rare DNA sequence variants in the Rhodopsin gene. This gene is involved in the pathogenesis of some retinal hereditary disorders as Retinitis Pigmentosa. These rare variants are G-->A at nucleotide 721 of the non-coding region and C-->T at nucleotide 5200 within codon 323 which does not alter the aminoacid cysteine. Therefore, they are not implicated in the development of the Retinitis Pigmentosa disease.

Adenine↗
PubMed2003

Evaluation of the Oculomedin gene in the etiology of primary open angle and exfoliative glaucoma.

PURPOSE: Glaucoma is a disease of the retinal ganglion cells leading to reduction of peripheral vision. It is often associated with an increase in intraocular pressure, leading to mechanical stress of tissues. The oculomedin gene is activated by such stretching and is therefore a candidate for causing glaucoma. METHODS: The coding sequence and part of the promoter was screened for sequence variants in Swedish cohorts of primary open angle glaucoma, exfoliative glaucoma, and matched controls. RESULTS: Only rare variants were detected in the patient material. CONCLUSIONS: There was no evidence that the oculomedin gene participates in the etiology of glaucoma.

Alleles↗
PubMed2004

RNA modulation, repair and remodeling by splice switching oligonucleotides.

Targeting splicing by antisense oligonucleotides allows RNA modifications that are not possible with RNA interference or other antisense techniques that destine the RNA for destruction. By changing the ratio of naturally occurring splice variants the expression of mRNA is modulated. By preventing the use of an aberrant splice site created by a mutation and enforcing re-selection of correct splice sites the RNA is repaired. Antisense induced skipping of the exon that carries a nonsense mutation remodels the mRNA and restores the reading frame of the defective protein. All of the above approaches have clinical applications. Modulation of splice variants is particularly important since close to 60% of all genes code for alternatively spliced pre-mRNA.

Alternative Splicing↗
PubMed2003

Potential species identification by allozyme/protein markers in European spined loaches.

Samples from 37 populations of spined loach (Cobitis) pure species and their hybrid complexes - were examined using gel electrophoresis for the interspecific variability in 27 protein coding loci. Up to now, species-specific and species distinguishing variants in different protein/enzyme loci were found in Cobitis bilineata, C. elongata, C. elongatoides, C. cf. fahirae, C. strumicae, C. taenia, C. tanaitica, and C. turcica. The species-specific differences in the occurrence of such variants were found in 11 loci for these Cobitis species. This allowed us both identification of species and recognition of interspecific hybrids in many complexes. Besides this we were able in many cases of polyploid hybrids to estimate their genomic composition.

Animals↗
PubMed1992

Multiple variants of the human lymphocyte homing receptor CD44 generated by insertions at a single site in the extracellular domain.

The human CD44 cell-surface glycoprotein participates in a wide variety of cell-cell interactions including lymphocyte homing and tumor metastasis. The CD44 antigen is known to display extensive size heterogeneity when compared between different tissue sources although the structural basis for this variation is not yet clear. Recently, two further isotypes in addition to the basic hemopoietic form of the CD44 antigen have been cloned and sequenced and these have been found to contain all or part of a 200-400-base pair insert within the extracellular domain, suggesting that the characteristic heterogeneity in the molecule may be generated by a mechanism of alternative splicing. We have obtained further evidence for alternative splicing, and we report here the cloning and sequencing of six different CD44 sequence variants from a variety of cell lines using a combination of expression cloning and the polymerase chain reaction. Comparison of these variants indicates that each is probably assembled by the insertion of five different exon units in tandem into a discrete site within the membrane proximal region of the extracellular domain. One of the variants contains an exon that shares extensive amino acid sequence homology with a recently described rat CD44 variant that mediates tumor metastasis. Another variant contains a new exon that encodes a tandem repeat of the consensus sequence SG for covalent modification with chondroitin sulfate and is expressed predominantly on mammary tumors. We suggest that a mechanism of alternative exon splicing generates much of the observed structural heterogeneity of CD44 and that the particular set of CD44 variants expressed in a single cell may represent a precise postal code directing the final destination of migrating cells and metastatic tumors.

Amino Acid Sequence↗
PubMed2004

[Risk factors for skin melanoma: genetic factors probably more important than exposure to sunlight].

Pigmented naevi (moles) are increasingly regarded as risk factors for the development of melanoma. The probability of melanoma developing from congenital naevi is proportional to the volume of the naevi. The risk of melanoma development from large naevi (diameter > 20 cm) is already present in the early years of childhood. The most important risk factor is the higher number of acquired naevi. This applies particularly to dysplastic (also called clinically atypical) naevi that not only represent the highest risk group but are also considered potential melanoma precursors. The development of acquired naevi (including dysplastic naevi) is dependant on the degree of skin pigmentation. The role of sunlight (ultraviolet radiation) in the development of melanoma is less significant than is generally assumed. The indirect effect of sunlight on melanoma development is to stimulate naevogenesis. One of the risk-modifying genes is the gene coding for melanocortin-1-receptor (MC1R). The presence of some gene variants has been found to lead to changes in melanin synthesis and is associated with a higher risk of melanoma. Recent research has shown that dysplastic naevi synthesise more phaeomelanin. There are also strong indications that dysplastic naevus cells suffer from chronic oxidative stress. This situation can lead to hypermutability and genetical instability.

Humans↗
PubMed2006

Peripherin/RDS and VMD2 mutations in macular dystrophies with adult-onset vitelliform lesion.

PURPOSE: Adult-onset vitelliform macular dystrophy (AVMD) is a pleomorphic late-onset macular phenotype characterized by a central yellow deposit between the neural retina and retinal pigment epithelium. Mutations in the genes encoding peripherin/RDS and VMD2 have been previously reported in some subjects with AVMD. The purpose of this investigation was to determine the prevalence of mutations in these two genes in a cohort of cases with macular dystrophies presenting with vitelliform lesions in adulthood. METHODS: Fifty nine consecutively ascertained and unrelated subjects prospectively coded as pattern or vitelliform macular dystrophies were reviewed and twelve subjects with a vitelliform lesion were identified. Patient evaluation included comprehensive ocular examination, retinal imaging, and functional studies in selected subjects. The RDS and VMD2 genes were screened for variation by direct DNA sequencing of coding regions and intron/exon boundaries. RESULTS: Twenty-two DNA sequence variants were identified in the genes encoding RDS and VMD2. A Pro210Arg variant found in the RDS gene of one subject was the only definite mutation detected in either gene. CONCLUSIONS: The Pro210Arg mutation has been reported previously in patients with pattern dystrophy confirming the observation that pattern dystrophy can present with an AVMD phenotype. Although RDS and VMD2 are the only known genes with mutations contributing to AVMD, our series demonstrates that most patients have mutations in genes that have yet to be discovered.

Age of Onset↗
PubMed1991

Epitope analysis of cluster 1 and NK cell-related monoclonal antibodies.

By flow cytometric assays, we tested the antibodies of the Second International Workshop on Small Cell Lung Cancer Antigens against 20 normal peripheral leukocytes, four small cell lung cancer (SCLC) cell lines (one classic type, and three variant type) and one gastric cancer line (KATO 3). Thirteen antibodies (Code # 4, 12, 21, 31, 34, 41, 48, 58, 60, 61, 74, 77, 82) among 98 registered antibodies showed a very similar pattern to antibody NE150, which was previously characterised as SCLC cluster 1. Since NE150 showed a positive reaction to the natural killer (NK) cell population, the serological specificity was compared with NK cell-associated antibodies, NKH1 (CD56), Leu7 (CD57) and Leu11 (CD16). Only NKH1 antibody showed a similar pattern to NE150, when tested against various target cells including SCLC lines and peripheral leukocytes, suggesting that NKH1 is a cluster 1 antibody, although it was already classified as CD56 of hematopoietic cells. By sequential immunoprecipitation, the antigen detected by NE150 antibody was depleted by preincubation with NKH1 antibody, but the reactivity of NE150 was not inhibited by NKH1 antibody, suggesting that NE150 and NKH1 detect different epitopes on the same antigen molecule. Epitope analysis was also conducted with 13 antibodies of cluster 1. Ten were found to detect the same epitope as NE150. The other three did not inhibit the binding of NE150 or NKH1, suggesting that there are at least three epitopes. Since the cluster 1 antibodies were demonstrated to detect NCAM, the present results suggest the presence of at least three epitopes on this molecule.

Antibodies, Monoclonal↗